scholarly journals Comparison of Tumor Immune Environment Between Newly Diagnosed and Recurrent Glioblastoma in Matched Patients

2022 ◽  
Author(s):  
Fei Wang ◽  
Sahara J Cathcart ◽  
Dominick J DiMaio ◽  
Nan Zhao ◽  
Jie Chen ◽  
...  
Keyword(s):  
Tumor Infiltrating Lymphocytes ◽  
Distribution Patterns ◽  
Primary Brain Tumor ◽  
Primary Diagnosis ◽  
Recurrent Glioblastoma ◽  
Initial Diagnosis ◽  
Newly Diagnosed ◽  
Response To Chemotherapy ◽  
Tissue Specimens ◽  
Recurrent Gbm

Abstract Purpose: Glioblastoma (GBM) is the most lethal primary brain tumor in adult patients. The disease progression, response to chemotherapy and radiotherapy at initial diagnosis, and prognosis are profoundly associated with the tumor microenvironment (TME), especially the features of tumor-infiltrating immune cells (TII). Recurrent GBM is even more challenging to manage. Differences in the immune environment between newly diagnosed and recurrent GBM and an association with tumor prognosis are not well defined. Methods: To address this knowledge gap, we analyzed the clinical data and tissue specimens from 24 GBM patients (13 at initial diagnosis and 11 at recurrence). The expression levels of multiple immunobiological markers in patients’ GBM at initial diagnosis versus at recurrence were compared, including five patients with both specimens available (paired). The distribution patterns of TII were evaluated in both the intratumoral and perivascular regions. Results: We found that tumors from recurrent GBM have significantly more tumor-infiltrating lymphocytes (TILs) and macrophages and higher PD-L1 expression than tumors at primary diagnosis and benign brain specimens from epilepsy surgery. The pattern changes of the TILs and macrophages of the five paired specimens were consistent with the unpaired patients, while the CD8 to CD4 ratio remained constant from diagnosis to recurrence in the paired tissues. The levels of TILs and macrophages at initial diagnosis did not correlate with OS. TILs and macrophages were increased in recurrent tumors both in intratumoral and perivascular areas, with higher distribution levels in intratumoral than perivascular regions. Higher CD4 or CD8 infiltration at recurrence was associated with worse prognosis, respectively. Conclusion: Our study elucidated that TIL and TAM tend to accumulate in perivascular region and are more abundant in recurrent GBM than newly diagnosed GBM.

scholarly journals Laser interstitial thermal therapy for newly diagnosed and recurrent glioblastoma

2016 ◽  
Vol 41 (4) ◽  
pp. E12 ◽  
Author(s):  
Jonathan G. Thomas ◽  
Ganesh Rao ◽  
Yvonne Kew ◽  
Sujit S. Prabhu
Keyword(s):  
Median Survival ◽  
Progression Free Survival ◽  
Primary Brain Tumor ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Laser Interstitial Thermal Therapy ◽  
Median Progression Free Survival ◽  
Recurrent Gbm

OBJECTIVE Glioblastoma (GBM) is the most common and deadly malignant primary brain tumor. Better surgical therapies are needed for newly diagnosed GBMs that are difficult to resect and for GBMs that recur despite standard therapies. The authors reviewed their institutional experience of using laser interstitial thermal therapy (LITT) for the treatment of newly diagnosed or recurrent GBMs. METHODS This study reports on the pre-LITT characteristics and post-LITT outcomes of 8 patients with newly diagnosed GBMs and 13 patients with recurrent GBM who underwent LITT. RESULTS Compared with the group with recurrent GBMs, the patients with newly diagnosed GBMs who underwent LITT tended to be older (60.8 vs 48.9 years), harbored larger tumors (22.4 vs 14.6 cm3), and a greater proportion had IDH wild-type GBMs. In the newly diagnosed GBM group, the median progression-free survival and the median survival after the procedure were 2 months and 8 months, respectively, and no patient demonstrated radiographic shrinkage of the tumor on follow-up imaging. In the 13 patients with recurrent GBM, 5 demonstrated a response to LITT, with radiographic shrinkage of the tumor following ablation. The median progression-free survival was 5 months, and the median survival was greater than 7 months. CONCLUSIONS In carefully selected patients with recurrent GBM, LITT may be an effective alternative to surgery as a salvage treatment. Its role in the treatment of newly diagnosed unresectable GBMs is not established yet and requires further study.

scholarly journals CBMT-24. CHARACTERIZATION OF PRIMARY CILIUM IN RECURRENT GLIOBLASTOMA: IMPLICATIONS FOR NEW THERAPEUTIC TARGETS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi38-vi38
Author(s):  
Vittorio Stumpo ◽  
Aruljothi Marappian ◽  
Quintino Giorgio D’Alessandris ◽  
Simone Pacioni ◽  
Rina Di Bonaventura ◽  
...  
Keyword(s):  
Primary Cilium ◽  
Intracellular Signaling ◽  
Treatment Resistance ◽  
Recurrent Glioblastoma ◽  
Newly Diagnosed ◽  
Ciliated Cells ◽  
Differentiation Markers ◽  
Compensatory Response ◽  
Who Grade ◽  
Recurrent Gbm

Abstract INTRODUCTION Primary cilium is a highly conserved, dynamic cellular organelle which plays several roles in embryonic development, intracellular signaling, and cell cycle. Structural alterations of primary cilium have been described in human gliomas including glioblastoma (GBM), however, its actual role in pathogenesis and treatment resistance of these tumors is largely unknown. METHODS We investigated cilium morphology and expression of cilium-related genes in human glioma of various WHO grade and in couples of patient-derived glioma stem-like cells (GSCs) that were established from the very same GBM at first diagnosis and at recurrence. Immunohistochemistry with anti-Arl13b antibody was used to assess cilium morphology. The expression levels of genes involved in ciliary disassembly complex (CDC) were analyzed by quantitative real-time PCR, using neural progenitor cells (NPCs) as control. Lastly, we assessed 3 GSC cultures that were treated with a drug inhibiting cilia disassembly (CCB-Cil). RESULTS Anaplastic oligodendroglioma and proneural GBM showed the highest percentage of ciliated cells. In GBM, we found the highest percentage of fragmented cilia. GSCs derived from newly diagnosed GBMs displayed lower percentages of ciliated cells than those derived from recurrent GBMs (20% vs 70%). Morphological analysis indicated that GSCs from recurrent GBM show cilia with extremely various morphology compared with GSCs from newly diagnosed GBM and NPCs. Gene analysis showed reduced expression of CDC-related genes in GSCs from newly diagnosed GBM with respect to those from recurrent GBMs. CCB-Cil treatment determined a global reduction of CDC-related genes, increased expression of differentiation markers (GFAP), and reduction of stemness markers (SOX2). CONCLUSIONS The increased percentage of ciliated cells in GSCs from recurrent GBM may be related to a compensatory response of CDC and to an accelerated ciliary turnover. Blocking cilia disassembly reduces stemness features and induces differentiation in GSCs, suggesting that this approach could represent a promising strategy for targeting GBM.

Bevacizumab (BV) plus irinotecan (I) in recurrent glioblastoma multiforme (GBM): A single center experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13000-e13000
Author(s):  
Eluska Iruarrizaga ◽  
Eider Azkona ◽  
Unai Aresti ◽  
Itziar Rubio ◽  
Mikel Arruti ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Median Number ◽  
Primary Brain Tumor ◽  
Recurrent Glioblastoma ◽  
Recurrent Glioblastoma Multiforme ◽  
Single Center Experience ◽  
Flair Sequence ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Recurrent Gbm

e13000 Background: Glioblastoma multiforme constitutes the most common and malignant form of primary brain tumor. Median survival for recurrent disease is 3-9 months. Combining bevacizumab with irinotecan represents an option of treatment in recurrent GBM. Methods: We performed a retrospective review of patients with recurrent GBM treated with bevacizumab (10 mg/kg) and irinotecan (340 mg/m2 for patients receiving enzyme-inducing antiepileptic drugs –EIAEDs- and 125 mg/m2 for patients not receiving EIAEDs) every 14 days on a 4-week cycle. Inclusion criteria: age ≥ 18, histology of GBM, progression after radiotherapy and temozolomide and signed informed consent for bevacizumab compassionate use. MRI-FLAIR sequence was used every 8 weeks to assess response. Results: From October 2009 to December 2012, a total of 26 patients were included; 15 (57.7%) male/11 (42.3%) female. Median age of the patients was 52 years (32-69); ECOG 0/1/2/3: 7.7/46.2/38.5/7.7% respectively; 19.23 % of patients received EIAEDs. Median number of cycles was 2.5 (1-14). Response rate was 30.8% (23.1% PR; 7.7 % CR); SD 23.1 %. Median PFS was 23 weeks; median OS was 30 weeks. Most common grade 3 toxicities were: asthenia 26.9%, arthromyalgia 3.8%, diarrhea 3.8% and hepatotoxicity 15.4%; grade 2 thromboembolic complications: 3.8 %. Conclusions: Combination of bevacizumab and irinotecan is effective against recurrent GBM and prolongs PFS and OS compared with historical controls, with mild toxicity.

GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2074-TPS2074
Author(s):  
Patrick Y. Wen ◽  
Ingo K. Mellinghoff ◽  
Meredith Becker Buxton ◽  
Webster K. Cavenee ◽  
Howard Colman ◽  
...  
Keyword(s):  
Active Sites ◽  
Drug Application ◽  
Recurrent Glioblastoma ◽  
Pharmacokinetic Data ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Adaptive Randomization ◽  
New Drug ◽  
Multiple Drugs ◽  
Recurrent Gbm

TPS2074 Background: GBM AGILE, Glioblastoma Adaptive, Global, Innovative Learning Environment, is an international, multi-arm, seamless phase 2/3 response adaptive randomization platform trial designed to evaluate multiple therapies in newly diagnosed (ND) and recurrent glioblastoma (GBM) with the goal of identifying effective therapies matching them accurately to different patient subtypes in an accelerated manner. It is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. Methods: The primary objective of GBM AGILE is to identify therapies that effectively improve overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical companies to be evaluated simultaneously and/or over time against a common standard of care control. Based on performance, a drug may graduate and move to a rapid stage 2 (phase 3) within the trial, and the totality of the data can be used for a new drug application. An active pipeline is critical to the ongoing success of GBM AGILE. With the leadership of the trial’s Arm Selection Committee, uniform processes for including new drugs have been established to ensure a consistent review of drugs/drug combinations over the course of the trial. Factors considered include relevant pre-clinical data, preliminary evidence for antitumor activity. pharmacokinetic data to support proposed drug dosing and administration, and potential biomarkers helpful for the development of a drug. GBM AGILE provides an efficient mechanism to screen and develop robust information regarding the efficacy of proposed novel therapeutics and associated biomarkers for GBM and to quickly move therapies and biomarkers into clinic. GBM AGILE received IND approval from the FDA in April 2019, screening its first patient in June 2019. Site activation is ongoing in the US, with over 35 active sites and over 425 patients screened (as of February 2021). Expansion to Canada, Europe and China are under progress. Clinical trial information: NCT03970447.

scholarly journals Multiplex-inhibitor bead mass spectrometry reveals differential kinome signatures in newly diagnosed and recurrent glioblastoma

2020 ◽  
Author(s):  
Anna Jermakowicz ◽  
Alison M. Kurimchak ◽  
Jann Sarkaria ◽  
Ricardo Komotar ◽  
Michael E. Ivan ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Clinical Trials ◽  
Signaling Pathways ◽  
Surgical Resection ◽  
Kinase Inhibitors ◽  
Resistance Mechanisms ◽  
Recurrent Glioblastoma ◽  
Adult Brain ◽  
Newly Diagnosed ◽  
Recurrent Gbm

ABSTRACTGlioblastoma (GBM) is the most common and aggressive adult brain tumor. Despite years of research, clinical trials have not improved the outcome for GBM. Standard of care for newly diagnosed GBM includes surgical resection, followed by radiation and chemotherapy. Tumor recurrence is inevitable and since most patients are not candidates for a second surgical resection, there is an urgent need to identify resistance mechanisms that arise in recurrent GBM. We postulated that examining the differences of activated kinases between newly diagnosed and recurrent GBM may provide insight to resistance mechanisms.To map the kinome landscape of newly diagnosed (nGBM) and recurrent GBM (rGBM) patient derived xenograft tumors, we used Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). We performed pathway analysis of kinases that differed in MIB-binding between nGBM and rGBM to identify kinase-driven signaling pathways. We also analyzed transcriptional profiles to determine the overlap in signaling pathways seen using proteomics or transcriptomics.Using MIB-MS kinome profiling, we found key differences in kinase-driven signaling pathways that may account for the increase in aggressive behavior seen in recurrent GBM. This included a shift in pathways driving cell invasion and proliferation, as well as upregulation of signaling pathways that drive GBM stem-cell like cell differentiation. Analysis of RNA-sequencing showed no statistically significant differences between enriched gene ontologies in nGBM and rGBM, demonstrating the importance of MIB-MS kinome profiling. Collectively, these studies suggest that kinome profiling may inform future clinical trials for kinase inhibitors in GBM.

scholarly journals ATIM-11. TUMOR-INFILTRATING LYMPHOCYTES EXPRESSING ANTI-PD-1 ANTIBODY EXHIBIT A PROMISING EFFICACY AND SURVIVAL BENEFIT IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi3-vi4
Author(s):  
Chao Tang ◽  
Zhi Zhang ◽  
Di Chen ◽  
Kai Ji ◽  
Chunxia Ji ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Genomic Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Recurrent Glioblastoma ◽  
Autologous Tumor ◽  
Recurrent Glioblastoma Multiforme ◽  
Cell Therapies ◽  
Cutaneous Toxicities ◽  
Infiltrating Lymphocytes ◽  
Recurrent Gbm

Abstract Adoptive cell therapies utilizing autologous tumor-infiltrating lymphocytes (TIL) have been demonstrated to be safe and promising in anti-tumor activities; However, their efficiency was still low in treating glioblastoma multiforme (GBM) because of immunosuppression microenvironment. In this study, we proposed a new strategy to enhance the anti-tumor immune response by using modified TIL expressing anti-PD-1 antibody (anti-PD1-TIL), which could reverse immunosuppression in tumor microenviroment. From April 2017 to April 2018，a total of 8 patients with recurrent GBM were enrolled and received more than one cycles of anti-PD1-TIL immunotherapy after surgery and chemotherapy with a median follow-up of 20 months. The anti-PD1-TIL immunotherapy was well tolerated. Two patients suffered grade 1 and 2 adverse events, including fatigue, mucosal/cutaneous toxicities. The median overall survival time was 16.1（95% CL: 15.4–16.7）months. By iRANO criteria, one patient experienced a partial response (PR), and three patients experienced stable disease (SD) after anti-PD-1-TIL immunotherapy. Genomic analysis by whole exome sequencing revealed an enrichment of MUC12 mutation in responders (p< 0.01), and an enrichment of TMEM125 (p< 0.01) and HIST2H3A/C amplification (p< 0.05) associated with immunosuppressive signature in non-responders. Taken together, the anti-PD1-TIL immunotherapy is a safe and promising strategy with durable efficacy to treat patients with recurrent GBM. Clinicaltrials.gov identifier: NCT 03347097.

scholarly journals Treatment of Glioblastoma (GBM) with the Addition of Tumor-Treating Fields (TTF): A Review

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 174 ◽  
Author(s):  
Denise Fabian ◽  
Maria Guillermo Prieto Eibl ◽  
Iyad Alnahhas ◽  
Nikhil Sebastian ◽  
Pierre Giglio ◽  
...  
Keyword(s):  
Brain Tumor ◽  
First Generation ◽  
Standard Of Care ◽  
Primary Brain Tumor ◽  
Aggressive Treatment ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Tumor Treating Fields ◽  
Concomitant Chemoradiation ◽  
Recurrent Gbm

Glioblastoma (GBM) is the most common primary brain tumor. Despite aggressive treatment, GBM almost always recurs. The current standard-of-care for treatment of newly diagnosed GBM has remained relatively unchanged since 2005: maximal safe resection followed by concomitant chemoradiation (CRT) with temozolomide (TMZ), and subsequent adjuvant TMZ. In 2011, the first-generation tumor treating fields (TTF) device, known at the time as the NovoTTF-100A System (renamed Optune), was approved by the Food and Drug Administration (FDA) for treatment of recurrent GBM. The TTF device was subsequently approved as an adjuvant therapy for newly-diagnosed GBM in 2015. The following is a review of the TTF device, including evidence supporting its use and limitations.

scholarly journals CTNI-34. INITIAL ANALYSIS OF PHASE-III TRIAL - STANDARD CHEMOTHERAPY VS. CHEMOTHERAPY GUIDED BY A CANCER STEM CELL TEST IN RECURRENT GLIOBLASTOMA (NCT03632135)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii50-ii50
Author(s):  
Tulika Ranjan ◽  
Ricky Chen ◽  
Dawit Aregawi ◽  
Rekha Chaudhary ◽  
Soma Sengupta ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Standard Of Care ◽  
Recurrent Glioblastoma ◽  
Response To Therapy ◽  
Phase Iii ◽  
Initial Analysis ◽  
Response To Chemotherapy ◽  
Recurrent Gbm

Abstract BACKGROUND ChemoID is a cancer stem cell (CSC) cytotoxicity assay for guiding personalized treatment in the clinical trial NCT03632135 using standard-of-care drugs for improving clinical outcomes. The ChemoID assay is a functional test that determines the response to chemotherapy treatments from a panel of FDA approved drugs or their combinations. The trial aims to determine the clinical utility of the ChemoID assay as a predictor of clinical response in recurrent glioblastoma (GBM). METHODS The study has been designed as a parallel group controlled clinical trial where participants with recurrent GBM amenable to surgery or biopsy are randomized at a ratio of 1:1 to either standard-of-care chemotherapy chosen by the physician or ChemoID-guided therapy. Response to therapy is measured by MRI imaging (RANO 1.1). The primary endpoint is median overall survival (OS) and secondary endpoints are OS at 6, 9, and 12 months, median progression-free survival (PFS), PFS at 4, 6, 9, and 12 months, objective tumor response, time to recurrence, and quality of life. RESULTS A total of 41 participants (29 males, 12 females) have been accrued to the trial thus far with a median age of 61yo. Data from 38 participants (27 males, 11 females) has reached maturity for analysis. 21 participants have been randomized to the assay-guided arm and 17 to the physician-choice arm. From an initial analysis, we observed that 71% (15/21) of the participants in the ChemoID-guided arm are alive and 29% (6/21) are deceased. We also observed that 41% (7/17) of the participants in the physician-choice arm are alive and 59% (10/17) are deceased. This gives the odds of death for the ChemoID-guided arm to be 72% lower than on the physician-guided arm (OR=0.28; (0.07–1.08); p=0.065). CONCLUSIONS Our preliminary results indicate that the ChemoID assay has the potential to improve survival of recurrent GBM patients.

Use of immunotherapy in recurrent glioblastoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13523-e13523
Author(s):  
Ashley Love Sumrall ◽  
David Lowell Jennings ◽  
Daniel Ernest Haggstrom ◽  
James Thomas Symanowski
Keyword(s):  
Checkpoint Inhibitors ◽  
Staining Intensity ◽  
Recurrent Glioblastoma ◽  
Recurrent Tumor ◽  
Newly Diagnosed ◽  
Checkpoint Inhibition ◽  
Tumor Patients ◽  
Initial Tumor ◽  
Tumor Profiling ◽  
Recurrent Gbm

e13523 Background: With the recent explosion of interest in immunotherapy to treat cancer, it has moved into management of glioblastoma (GBM). Several trials are ongoing, investigating use of checkpoint inhibition for newly diagnosed and recurrent GBM. Methods: We reviewed the records of patients with recurrent glioblastoma (including gliosarcoma). Six of the eight patients demonstrated PD-1 positivity via immunohistochemical (IHC) staining. Two patients demonstrated PD-L1 positivity as 2+ staining intensity via IHC. Patients were managed with checkpoint inhibitors for at least four weeks. When feasible, patients had tumor profiling of initial tumor and recurrent tumor. Patients were followed for response, progression, and survival. Results: Eight patients were identified with recurrent GBM who received immunotherapy with checkpoint inhibitors. They ranged from first through fifth recurrence following radiation and temozolomide. Three patients received pembrolizumab. Of those, two were PD-L1 positive. Five patients received nivolumab, and all were PD-1 positive. There were no partial or complete responses. Five of the eight subjects died, and the median survival time among the 8 subjects was 3.6 months. Six of eight subjects progressed on treatment, and the median PFS was 2.2 months. Bevacizumab was given to two patients for suspected “tumor flare” while on nivolumab. Four of the eight patients had tumor profiling completed at initial diagnosis and recurrence. Treatment was well-tolerated with only minimal toxicity observed. Conclusions: Despite increasing interest in utilizing these medications for recurrent glioblastoma, overall survival in our cohort was consistent with historical control (3 to 5 months). Additionally, we did not witness any responses.

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